The broad objective of this project is to elucidate the mechanisms that mediate Muller cell responses to pathophysiological conditions in the human retina. Our long-range goal is to understand the role of ion channels in regulating the responses of Muller cells to changes in the extracellular environment. While earlier considerations assumed a static physiology for Muller cells, we recently found that certain potassium channels, i.e. KIR, are inhibited when human Muller cells are exposed to an agonist of glutamate, which may be in the high concentrations in the ischemic retina, or to thrombin, which may enter the retina with a breakdown of the blood-retinal barrier. The inhibition of these ion channels is likely to be of functional significance since they are involved in potassium homeostasis. We have also discovered that Muller cells of the human macula may be physiologically different than those of the well-studied amphibian retina in which excess retinal K+ enters the distal parts of the Muller cell and exits via its endfoot into the vitreous. In contrast, our electrophysiological experiments indicate that the endfoot of a macular Muller cell may be functionally isolated from the soma and distal regions. However, we also find that the soma-endfoot interactions in macular Muller cells can be enhanced by altering the K+ channel activity of these glia. Taken together, our findings raise the possibility that extracellular molecules which induce changes in the activity of K+ channels may regulate the soma-to-endfoot pathway for the removal of excess retinal K+. Simultaneous electrophysiological recordings from the somas and endfeet of Muller cells freshly dissociated from the human macula will allow direct measurements of the effects of extracellular molecules on the soma-endfoot interaction. Also, based on preliminary findings, various electrophysiological paradigms will be used to test the hypothesis that protein kinase C plays a role in mediating the potassium channel inhibition that occurs when human Muller cells are exposed to thrombin or the glutamate agonist NMDA. Knowledge of the mechanisms regulating K+ homeostasis in the macula may help us gain insights concerning retinal pathobiology.